P868: A CIRCULATING SERUM MIRNAS-BASED MODEL TO PREDICT EARLY MORTALITY IN MULTIPLE MYELOMA PATIENTS TREATED WITH BORTEZOMIB-BASED REGIMENS.
Authors: A. Puła, P. Robak, D. Jarych, D. Mikulski, I. Dróżdż, J. Szemraj, T. Robak
Journal: HemaSphere (2022)

Background: Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow. Despite the progress made in the treatment of MM, some patients die within the first year of diagnosis. Numerous studies underline the role of miRNAs in the pathogenesis of MM and their potential role in prognosis. Aims: The aim of this study was to analyze the expression of selected miRNAs in the serum of MM patients treated with bortezomib-based regimens and determine their potential to predict early mortality. Methods: The study was conducted in prospectively-recruited patients with newly-diagnosed MM who were qualified for bortezomib-based treatment regimens. All were admitted to the Department of Hematology, Medical University of Lodz between 2017 and 2021. Venous blood samples were collected from the patients before treatment initiation, processed, and stored for further use. Total RNA, including miRNA, was isolated from serum, and reverse-transcribed to cDNA. The expression of 31 selected miRNAs was determined using a miRCURY LNA miRNA Custom PCR Panel. The miRNA selection was based on the results of our previous study (Robak et al., Cancers Cancers (Basel) 2020; 12(9): 2569). Three miRNAs were used for expression normalization: hsa-miR-23b-3p, hsa-miR-151a-5p and hsa-miR-152-3p. Clinical data, including patient characteristics on diagnosis, treatment regimen, response to treatment and follow-up were obtained from hospital records. Differential expression analysis, univariate and multivariate logistic regression models were performed using R version 3.6.3. Results: A total of 69 MM patients were included in the study with a mean age at diagnosis of 64.9 ± 11.0 years. Among them, 17 patients experienced death within 12 months of diagnosis. Patients with early mortality were significantly older (72.6 vs. 62.3 years, p=0.0005), and more frequently men (70.6% vs. 42.3%, p=0.0429). No differences were observed in R-ISS distribution or CRAB symptoms between the groups, nor were any significant differences between percentage myeloma infiltration in the bone marrow and various laboratory findings, including LDH, serum M protein, albumin, CRP, and uric acid. In the differential expression analysis, two miRNAs were significantly downregulated in early mortality group- hsa-miR-328-3p (fold change- FC: 0.72, p=0.0342) and hsa-miR-409-3p (FC: 0.49, p=0.0357). Similarly, hsa-miR-328-3p (OR 0.44, 95%CI: 0.20-0.97, p=0.0415) and hsa-miR-409-3p (OR 0.69, 95%CI: 0.48-0.98, p=0.0400) were found to have a protective effect against early mortality in univariate analyses. The multivariate logistic regression analysis found that miRNAs retained their significance when established clinical prognostic factors were included. The final model consisted of hsa-miR-409-3p (OR 0.61, 95%CI: 0.37-0.99, p=0.0480), hsa-miR-328-3p (OR 0.33, 95%CI: 0.13-0.87, p=0.0254), age (OR 1.13, 95%CI: 1.03-1.23, p=0.0096) and R-ISS 3 (OR 2.91, 95%CI: 0.63-13.47, p=0.1723). A receiver operating characteristics (ROC) analysis for the model yielded an area under the curve (AUC) of 0.863 (95%CI: 0.761-0.965). At the optimal cut-off value of 0.28, the sensitivity and specificity reached 88.2% and 77.5%, respectively. Image:Summary/Conclusion: hsa-miR-409-3p and hsa-miR-328-3p are independent factors related to early mortality in MM patients. Our results were used to generate a multiple regression model that may have the potential to predict early mortality. Further external validation of our model is necessary to confirm its clinical value.